Designing and discovering compounds for dual-target inhibitors is challenging to synthesize new, safer, and more efficient drugs than single-target drugs, especially to treat multifactorial diseases such as cancer. The simulta-neous regulation of multiple targets might represent an alternative synthetic approach to optimize patient compliance and tolerance, minimizing the risk of target-based drug resistance due to the modulation of a few targets. To this end, we conceived for the first time the design and synthesis of dual-ligands sigma R/HDACi to evaluate possible employment as innovative candidates to address this complex disease. Among all synthesized compounds screened for several tumoral cell lines, compound 6 (K-i sigma R-1 = 38 +/- 3.7; K-i sigma R-2 = 2917 +/- 769 and HDACs IC50 = 0.59 mu M) is the most promising candidate as an antiproliferative agent with an IC50 of 0.9 mu M on the HCT116 cell line and no significant toxicity to normal cells. Studies of molecular docking, which confirmed the affinity over sigma R-1 and a pan-HDACs inhibitory behavior, support a possible balanced affinity and activity between both targets.

Discovery of first novel sigma/HDACi dual-ligands with a potent in vitro antiproliferative activity

Barbaraci, Carla;Patamia, Vincenzo;Rocca, Roberta;Dichiara, Maria;Zagni, Chiara;Pasquinucci, Lorella;Parenti, Carmela;Amata, Emanuele;Rescifina, Antonio;Marrazzo, Agostino
2023-01-01

Abstract

Designing and discovering compounds for dual-target inhibitors is challenging to synthesize new, safer, and more efficient drugs than single-target drugs, especially to treat multifactorial diseases such as cancer. The simulta-neous regulation of multiple targets might represent an alternative synthetic approach to optimize patient compliance and tolerance, minimizing the risk of target-based drug resistance due to the modulation of a few targets. To this end, we conceived for the first time the design and synthesis of dual-ligands sigma R/HDACi to evaluate possible employment as innovative candidates to address this complex disease. Among all synthesized compounds screened for several tumoral cell lines, compound 6 (K-i sigma R-1 = 38 +/- 3.7; K-i sigma R-2 = 2917 +/- 769 and HDACs IC50 = 0.59 mu M) is the most promising candidate as an antiproliferative agent with an IC50 of 0.9 mu M on the HCT116 cell line and no significant toxicity to normal cells. Studies of molecular docking, which confirmed the affinity over sigma R-1 and a pan-HDACs inhibitory behavior, support a possible balanced affinity and activity between both targets.
2023
Cancer
Dual-Ligands
HDAC enzyme
Multifactorial diseases
σ(1) Receptor
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.11769/580441
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